Interleukin-18 gene polymorphisms and rheumatoid arthritis: A meta-analysis

Interleukin-18 (IL-18) is a member of the IL-1 superfamily that enhances both innate and acquired immune responses. IL-18 is highly expressed in sera, synovial fluids and synovial tissues of patients with RA, and these IL-18 levels are correlated with RA disease activity, indicating an important role of IL-18 in the pathogenesis of RA. Several studies have examined the association of IL-18 gene polymorphisms with RA, but these studies have shown inconclusive and controversial results. To verify the association between IL-18 gene polymorphism and susceptibility to RA, we conducted a meta-analysis of all relevant reports cited in MEDLINE/PubMed before October 2012. A meta-analysis on the association between the IL-18 rs1946518 SNP and RA was performed for 2944 patients with RA and 2377 controls from 7 published studies and a meta-analysis on the association between the IL-18 rs187238 SNP and RA was performed for 1319 patients with RA and 1211 controls from 5 published studies. In addition, 2 studies involving 1873 RA patients and 1092 controls were considered in the meta-analysis of the association between the IL-18 rs360722 SNP and RA. No significant association was found between two IL-18 SNPs (rs1946518 and rs187238) and RA susceptibility in all subjects. In subgroup analysis stratified by ethnicity, there was still no significant association between these two IL-18 SNPs and RA susceptibility. However, the frequency of the T allele at rs360722 was found to be significantly lower in patients with RA compared with controls, although this finding was based on only 2 studies. The results of our meta-analysis suggest that IL-18 rs360722 SNP is only associated with RA susceptibility. However, due to only two studies included in our meta-analysis, large-scale well designed studies should be considered in future studies to confirm the exact role of IL-18 rs360722 SNP in RA susceptibility.     

A worm rich in protein: Quantitative,differential, and global proteomics in Caenorhabditis elegans

The nematode Caenorhabditis elegans (C. elegans) has been used with much success to study a number of biological processes. Although mostly known for its powerful forward and reverse genetics, work from many different groups over the past years has allowed this model organism to develop into a respectable system for proteomics studies as well. Large-scale survey studies led to improved genome annotation and to the generation of proteome catalogs, which set the stage for subsequent targeted proteomics studies. A number of focused comparative studies contributed to a better understanding of insulin signaling, spermatogenesis, oogenesis, and differential gene expression during development. In addition, C. elegans subproteomes and posttranslational modifications like glycosylation and phosphorylation have been identified. Here we describe the history of C. elegans proteomics, and provide a survey of the different methods that have been applied for relative and absolute quantification in comparative and global protein profiling studies in the worm. These studies suggest that C. elegans will provide a rich trove for “worm proteomicists”.     

Serum Anticholinergic Activity and Cognitive and Functional Adverse Outcomes in Older People: A Systematic Review and Meta-Analysis of the Literature

Introduction

Studies have reported associations between serum anticholinergic activity (SAA) and decline in cognitive performance, delirium, and functional impairment. The aim of this meta-analysis was to explore and quantify associations between SAA and adverse cognitive and functional outcomes in older people.

Materials and Methods

A literature search in Ovid MEDLINE, EMBASE, PsycINFO and IPA from 1946–2014 was completed. The primary outcomes of interest were cognitive and functional adverse outcomes associated with SAA in older people aged 55 years and above. The Cochrane Risk-Bias assessment tool was used to assess bias in randomised controlled trials (RCTs). The Newcastle-Ottawa Scale was used to assess the quality of non-RCTs. Meta-analyses were conducted for RCTs and cohort studies separately. Heterogeneity was assessed using I² tests.

Results

The primary electronic literature search identified a total of 1559 records in the 4 different databases. On the basis of full-text analysis, 33 studies that met the inclusion criteria. The review included 4 RCTs, 5 prospective cohort studies, 3 longitudinal cohort studies, 17 cross-sectional studies, and 4 case-control studies. Twenty-four of the retrieved studies examined an association between SAA and cognitive outcomes, 2 studies examined an association with SAA and functional outcomes and 8 studies examined associations between SAA and both cognitive, and functional outcomes. The meta-analysis on 4 RCTs showed no association with higher SAA and cognitive performance (I² = 89.38%, H² = 25.53 and p-value = <0.05) however, the pooled data from 4 observational studies showed elevated SAA was associated with reduced cognitive performance (I² = 0.00%, H² = 3.37 and p-value = 0.34).

Conclusion

This systematic review summarises the limitations of the SAA on predicting cognitive and functional outcomes in older people. SAA measured by receptor bioassay is flawed and its use in older people with multimorbidity and polypharmacy is questionable.     

Efficacy of cannabinoids against glioblastoma multiforme: A systematic review

IntroductionThe increased incidence of Glioblastoma Multiforme, the most aggressive and most common primary brain tumour, is evident worldwide. Survival rates are reaching only 15 months due to its high recurrence and resistance to current combination therapies including oncotomy, radiotherapy and chemotherapy. Light has been shed in the recent years on the anticancer properties of cannabinoids from Cannabis sativa.ObjectiveTo determine whether cannabinoids alone or in combination with radiotherapy and/or chemotherapy inhibit tumour progression, induce cancer cell death, inhibit metastasis and invasiveness and the mechanisms that underlie these actions.MethodPubMed and Web of Science were used for a systemic search to find studies on the anticancer effects of natural cannabinoids on glioma cancer cells in vitro and/or in vivo.ResultsA total of 302 papers were identified, of which 14 studies were found to fit the inclusion criteria. 5 studies were conducted in vitro, 2 in vivo and 7 were both in vivo and in vitro. 3 studies examined the efficacy of CBD, THC and TMZ, 1 study examined CBD and radiation, 2 studies examined efficacy of THC only and 3 studies examined the efficacy of CBD only. 1 study examined the efficacy of CBD, THC and radiotherapy, 2 studies examined the combination of CBD and THC and 2 more studies examined the efficacy of CBD and TMZ.ConclusionThe evidence in this systematic review leads to the conclusion that cannabinoids possess anticancer potencies against glioma cells, however this effect varies with the combinations and dosages used. Studies so far were conducted on cells in culture and on mice as well as a small number of studies that were conducted on humans. Hence in order to have more accurate results, higher quality studies mainly including human clinical trials with larger sample sizes are necessitated urgently for GBM treatment.     

A Meta-Analysis of Reference Values of Leptin Concentration in Healthy Postmenopausal Women

Objective

There are numerous reports about the leptin concentration (LC) in postmenopausal women (PW). Changes in LC can elicit different clinical outcomes. We systematically analyzed the LC in PW.

Methods

A search was conducted in original English-language studies published from 1994 to October 2012 in the following databases: Medline (78), Cochrane Center (123) Embase (505), Biological abstracts (108), Cochrane (53) and Science Finder Scholar (0). A meta-analysis was undertaken on the correction coefficient (r) between the serum LC and body mass index (BMI) for healthy PW across studies containing a dataset and sample size. Pre-analytical and analytical variations were examined. Pre-analytical variables included fasting status (FS) and sampling timing. Analytical variation comprised assay methodology, LC in those undertaking hormone replacement therapy (HRT) and those not having HRT as well as LC change according to age.

Results

Twenty-seven studies met the inclusion criteria. Eighteen studies detected LC in the morning in a FS, 15 studies denoted the r between leptin and the BMI. A combined r was counted for the 15 studies (r = 0.51 [95% confidence interval (CI), 0.46–0.54], P = 0.025), and if sampling collection was in the FSat morning, a combined r was form 10 studies (r = 0.54 [95% CI, 0.45–0.54], P = 0.299) and heterogeneity was diminished. LC did not change between HRT users and non-users in 7 studies. Five studies analyzed changes in LC according to age.

Conclusion

Based on all studies that investigated both LC and BMI, LC was positively correlated with the BMI. No studies established reference ranges according to the Clinical and Laboratory Standards Institute (CLSI) in healthy PW, and there was a wide variation in LC values. These differences suggest that caution should be used in the interpretation and comparison between studies.     

Tuberculosis as a complex trait: impact of genetic epidemiological study design

Several studies have suggested a role for human genetic risk factors in the susceptibility to developing tuberculosis (TB). However, results of these studies have been inconsistent, and one potential reason for these inconsistencies is variation in aspects of study design. Specifically, phenotype definitions and population genetic factors have varied dramatically. Since TB is a complex trait, there are many challenges in designing studies to assess appropriately human genetic risk factors for the development of TB as opposed to the acquisition of latent M. tuberculosis infection. In this review we summarize these important study design differences, with illustrations from the TB genetics literature. We cite specific examples of studies of the NRAMP1 (SLC11A1) gene and present Fisher??s combined p values for different stratifications of these studies to further illustrate the impact of study design differences. Finally, we provide suggestions for the design of future genetic epidemiological studies of TB.     

DCC: Is there a connection between tumorigenesis and cell guidance molecules?

Based on the findings reviewed above, DCC remains a strong candidate for the tumor suppressor gene in the 18q21 region that is presumed to be frequently inactivated in colorectal and a number of other cancer types. Although little is known of the specific mechanisms that account for the loss of its expression in most cancers, the recent studies demonstrating an association between loss of DCC expression in colorectal cancers and poor prognosis imply that DCC inactivation may have very significant effects on the cancer cell phenotype. DCC function in normal and cancer cells is still relatively poorly understood. However, recent studies have begun to provide some insights. Based on the results of a number of recent studies, DCC appears likely to have a role in significant role in differentiation, cell fate determination, and migration in the nervous system and perhaps other tissues as well. Though many additional studies are needed to characterize DCC function more definitively, it seems reasonable to predict that such studies are likely to provide new insights into growth control pathways in normal and cancer tissues.     

Sox2 roles in neural stem cells

Throughout vertebrate evolution, Sox2 marks the developing nervous system from its earliest developmental stages and, therein, the most undifferentiated precursor cells, including stem cells. Recent gene targeting studies investigated the function of Sox2 in two neuronal systems: the developing eye and brain. These studies uncovered a requirement for Sox2 in the maintenance of neural stem cells, as well as a downstream role in the differentiation of specific neuron sub-types. In both systems, Sox2 action is markedly dose-dependent, and downstream-target gene studies are beginning to reveal the mechanisms of Sox2 function.     

Prevalence of Leishmania RNA virus in Leishmania parasites in patients with tegumentary leishmaniasis: A systematic review and meta-analysis

BackgroundCutaneous leishmaniasis is caused by different protozoan parasites of the genus Leishmania. Leishmania RNA virus (LRV) was identified as the first Leishmania infecting virus in 1998. Different studies showed the presence and role of the LRV in Leishmania parasites causing cutaneous leishmaniasis (CL). However, there is limited data on the pooled prevalence of LRV in Leishmania parasites causing CL. Therefore, the aim of this systematic review and meta-analysis was to determine the pooled prevalence of LRV in Leishmania parasite isolates and/or lesion biopsies in patients with CL from the available literature globally.MethodologyWe retrieved the studies from different electronic databases. The studies were screened and identified based on the inclusion and exclusion criteria. We excluded studies exclusively done in experimental animals and in vitro studies. The review was conducted in line with PRISMA guidelines. The meta-analysis was performed with Stata software version 14 with metan command. The forest plot with random-effect model was used to estimate the pooled prevalence with 95% confidence interval. Inverse variance index (I²) was used to assess the heterogeneity among the included articles.Principal findingsA total of 1215 samples from 25 studies were included. Of these, 40.1% (487/1215) were positive for LRV. The overall pooled prevalence of LRV globally was 37.22% (95% CI: 27.54% - 46.90%). The pooled prevalence of LRV in the New World (NW) and Old World (OW) regions was 34.18% and 45.77%, respectively. Leishmania guyanensis, L. braziliensis, L. major, and L. tropica were the most studied species for the detection of LRV. The prevalence of LRV from Leishmania isolates and lesion biopsies was 42.9% (349/813) and 34.3% (138/402), respectively.ConclusionThis systematic study revealed that there is high prevalence of LRV in Leishmania parasites isolated from patients with CL. More comprehensive studies would be required to investigate the presence of the LRV in other Leishmania species such as L. aethiopica to fully understand the role of LRV in different clinical manifestations and disease pathology presented in CL patients.     

A scoping review of burden of disease studies estimating disability-adjusted life years due to Taenia solium

BackgroundTaenia solium is the most significant global foodborne parasite and the leading cause of preventable human epilepsy in low and middle-income countries in the form of neurocysticercosis.ObjectivesThis scoping review aimed to examine the methodology of peer-reviewed studies that estimate the burden of T. solium using disability-adjusted life years.Eligibility criteriaStudies must have calculated disability-adjusted life years relating to T. solium.Charting methodsThe review process was managed by a single reviewer using Rayyan. Published data relating to disease models, data sources, disability-adjusted life years, sensitivity, uncertainty, missing data, and key limitations were collected.Results15 studies were included for review, with seven global and eight national or sub-national estimates. Studies primarily employed attributional disease models that relied on measuring the occurrence of epilepsy before applying an attributable fraction to estimate the occurrence of neurocysticercosis-associated epilepsy. This method relies heavily on the extrapolation of observational studies across populations and time periods; however, it is currently required due to the difficulties in diagnosing neurocysticercosis. Studies discussed that a lack of data was a key limitation and their results likely underestimate the true burden of T. solium. Methods to calculate disability-adjusted life years varied across studies with differences in approaches to time discounting, age weighting, years of life lost, and years of life lived with disability. Such differences limit the ability to compare estimates between studies.ConclusionsThis review illustrates the complexities associated with T. solium burden of disease studies and highlights the potential need for a burden of disease reporting framework. The burden of T. solium is likely underestimated due to the challenges in diagnosing neurocysticercosis and a lack of available data. Advancement in diagnostics, further observational studies, and new approaches to parameterising disease models are required if estimates are to improve.     

Complete Genome Sequence of Bacillus subtilis Strain QB928, a Strain Widely Used in B. subtilis Genetic Studies

The complete genome sequence of Bacillus subtilis strain QB928 was constructed to facilitate studies in the evolution of the genetic code. With a widespread use of the strain in Bacillus subtilis genetics studies, its complete genome sequence would facilitate deeper understanding of Bacillus subtilis genetics.     

The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: A paradigm for the development of other macromolecular markers-A review

Seven years after the initial studies of the prognostic value of the proto-oncogene c-erbB-2 in breast cancer, its role is still being defined. The interpretation of studies on the use of this gene and its protein product in prognostic and predictive tests for breast cancer is complicated by multiple methodologies and the inherent difficulties in the studies. The work has moved beyond the stage at which small studies with short follow-up (useful for hypothesis generation) are of value, to the stage in which large studies with sufficient statistical power to find significant correlations are central. These larger studies do not lend support for the use of c-erbB-2 in the evaluation of axillary-node-negative patients, the group of breast cancer patients for whom refinement of prognostic estimates is now most important. There are, however, hints that c-erbB-2 may have value in predicting response to certain treatments, though the studies so far are too few, often too small and too conflicting to reliably confirm this.     

Comparative leaf anatomy and morphology of some neotropical Rutaceae: Pilocarpus Vahl and related genera

Previous anatomical studies have been restricted to the foliar aspects of Pilocarpus. However, no anatomical studies analyzing the foliar aspects of Pilocarpus in relation to related genera have been carried out. Therefore, the aim of this study was to identify characters for future taxonomic and phylogenetic studies in Rutaceae, particularly in Pilocarpus, and to discuss the characteristics associated with the simple or compound leaf condition for the group. The petiole and the leaf blade of 14 neotropical Rutaceae species were analyzed, and the following characteristics were observed in all leaves studied: stomata on both surfaces; secretory cavities, including mesophyll type; camptodromous?Cbrochidodromous venation pattern; and free vascular cylinder in the basal region of the petiole. Additional promising characters were identified for future taxonomic and phylogenetic studies in the Rutaceae family, especially for the Pilocarpus genera.     

Extrapolating non-target risk of Bt crops from laboratory to field

The tiered approach to assessing ecological risk of insect-resistant transgenic crops assumes that lower tier laboratory studies, which expose surrogate non-target organisms to high doses of insecticidal proteins, can detect harmful effects that might be manifested in the field. To test this assumption, we performed meta-analyses comparing results for non-target invertebrates exposed to Bacillus thuringiensis (Bt) Cry proteins in laboratory studies with results derived from independent field studies examining effects on the abundance of non-target invertebrates. For Lepidopteran-active Cry proteins, laboratory studies correctly predicted the reduced field abundance of non-target Lepidoptera. However, laboratory studies incorporating tri-trophic interactions of Bt plants, herbivores and parasitoids were better correlated with the decreased field abundance of parasitoids than were direct-exposure assays. For predators, laboratory tri-trophic studies predicted reduced abundances that were not realized in field studies and thus overestimated ecological risk. Exposure to Coleopteran-active Cry proteins did not significantly reduce the laboratory survival or field abundance of any functional group examined. Our findings support the assumption that laboratory studies of transgenic insecticidal crops show effects that are either consistent with, or more conservative than, those found in field studies, with the important caveat that laboratory studies should explore all ecologically relevant routes of exposure.     

Shoulder biomechanics of RC repair and Instability: A systematic review of cadaveric methodology

BackgroundNumerous biomechanical studies have addressed normal shoulder function and the factors that affect it. While these investigations include a mix of in-vivo clinical reports, ex-vivo cadaveric studies, and computer-based simulations, each has its own strengths and limitations. A robust methodology is essential in cadaveric work but does not always come easily. Precise quantitative measurements are difficult in in-vivo studies, and simulation studies require validation steps. This review focuses on ex-vivo cadaveric studies to emphasize the best research methodologies available to simulate physiologically and clinically relevant shoulder motion.MethodsA PubMed and Web of Science search was conducted in March 2017 (and updated in May 2018) to identify the cadaveric studies focused on the shoulder and its function. The key words for this search included rotator cuff (RC) injuries, RC surgery, and their synonyms. The protocol of the study was registered on PROSPERO and is accessible at CRD42017068873.ResultsThirty one studies consisting of 167 specimens with various biomechanical methods met our inclusion criteria. All studies were level V cadaveric studies. Cadaveric biomechanical models are widely used to study shoulder instability and RC repair. These models are commonly limited to the glenohumeral joint by a fixed scapula, passively and discretely move the humerus, and statically load the RC without regard for the integrity of the glenohumeral capsule.ConclusionAll studies captured in this review evaluated shoulder biomechanics. Recent studies in patients suggest that some assumptions made in this space may not fully characterize motion of the human shoulder. With reproducible scapular positioning, dynamic RC activation, and preservation of glenohumeral capsule integrity, cadaveric studies can facilitate proper validation for simulation models and broaden our understanding of the shoulder environment during motion in healthy and disease states.     

Programmed Cell Death-1 Polymorphisms Decrease the Cancer Risk: A Meta-Analysis Involving Twelve Case-Control Studies

Programmed cell death-1 (PD-1) plays an important inhibitory role in anti-tumor responses, so it is considered as a powerful candidate gene for individual’s genetic susceptibility to cancer. Recently, some epidemiological studies have evaluated the association between PD-1 polymorphisms and cancer risk. However, the results of the studies are conflicting. Therefore, a meta-analysis was performed. We identified all studies reporting the relationship between PD-1 polymorphisms and cancers by electronically searches. According to the inclusion criteria and the quality assessment of Newcastle-Ottawa Scale (NOS), only high quality studies were included. A total of twelve relevant studies involving 5,206 cases and 5,174 controls were recruited. For PD-1.5 (rs2227981) polymorphism, significantly decreased cancer risks were obtained among overall population, Asians subgroup and population-based subgroup both in TT vs. CC and TT vs. CT+CC genetic models. In addition, a similar result was also found in T vs. C allele for overall population. However, there were no significant associations between either PD-1.9 (rs2227982) or PD-1 rs7421861 polymorphisms and cancer risks in all genetic models and alleles. For PD-1.3 (rs11568821) polymorphism, we found different cancer susceptibilities between GA vs. GG and AA vs. AG+GG genetic models, and no associations between AA vs. GG, AA+AG vs. GG genetic models or A vs. G allele and cancer risks. In general, our results firstly indicated that PD-1.5 (rs2227981) polymorphism is associated a strongly decreased risk of cancers. Additional epidemiological studies are needed to confirm our findings.     

N-ethyl-N-Nitrosourea (ENU) Induced Mutations within the Klotho Gene Lead to Ectopic Calcification and Reduced Lifespan in Mouse Models

Ectopic calcification (EC), which is the pathological deposition of calcium and phosphate in extra-skeletal tissues, may be associated with hypercalcaemic and hyperphosphataemic disorders, or it may occur in the absence of metabolic abnormalities. In addition, EC may be inherited as part of several monogenic disorders and studies of these have provided valuable insights into the metabolic pathways regulating mineral metabolism. For example, studies of tumoural calcinosis, a disorder characterised by hyperphosphataemia and progressive EC, have revealed mutations of fibroblast growth factor 23 (FGF23), polypeptide N-acetyl galactosaminyltransferase 3 (GALNT3) and klotho (KL), which are all part of a phosphate-regulating pathway. However, such studies in humans are limited by the lack of available large families with EC, and to facilitate such studies we assessed the progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for EC. This identified two mutants with autosomal recessive forms of EC, and reduced lifespan, designated Ecalc1 and Ecalc2. Genetic mapping localized the Ecalc1 and Ecalc2 loci to a 11.0 Mb region on chromosome 5 that contained the klotho gene (Kl), and DNA sequence analysis identified nonsense (Gln203Stop) and missense (Ile604Asn) Kl mutations in Ecalc1 and Ecalc2 mice, respectively. The Gln203Stop mutation, located in KL1 domain, was severely hypomorphic and led to a 17-fold reduction of renal Kl expression. The Ile604Asn mutation, located in KL2 domain, was predicted to impair klotho protein stability and in vitro expression studies in COS-7 cells revealed endoplasmic reticulum retention of the Ile604Asn mutant. Further phenotype studies undertaken in Ecalc1 (kl^203X/203X) mice demonstrated elevations in plasma concentrations of phosphate, FGF23 and 1,25-dihydroxyvitamin D. Thus, two allelic variants of Kl that develop EC and represent mouse models for tumoural calcinosis have been established.     

Significant association between GSTT1 null genotype and susceptibility to pancreatic cancer

Many studies have investigated the association between glutathione S-transferase T1 (GSTT1) polymorphism and risk for pancreatic cancer, but those studies have yielded contradictory findings on the association. We performed a comprehensive search in the PubMed, EMBASE, and the Chinese National Knowledge Infrastructure databases to identify relevant studies. A meta-analysis was performed to examine the association between GSTT1 polymorphism and susceptibility to pancreatic cancer by calculating the pooled odds ratios (ORs) and corresponding 95 % confidence intervals (95 % CIs). Eight studies involving a total of 4,437 individuals were included. Overall, significantly increased pancreatic cancer risk was associated with GSTT1 null genotype when all studies were pooled into the meta-analysis (random effects OR = 1.61, 95 % CI 1.06–2.44; P = 0.025). Significantly increased risk of pancreatic cancer was also found for GSTT1 null genotype in Asians when stratified by ethnicity (fixed effects OR = 2.67, 95 % CI 1.74–4.09; P < 0.001). The findings demonstrate that GSTT1 null genotype have a modest effect on the genetic susceptibility to pancreatic cancer, and GSTT1 null genotype is associated with increased risk of pancreatic cancer.     

Molecular mechanism of RNA phage morphogenesis

Recent progress on the molecular mechanism of RNA phage morphogenesis is described. Functional studies, both in vivo and in vitro, are correlated with the latest structural studies on phages, their capsids and the assembly initiation RNA stem-loop.